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VGLL4 promotes vascular endothelium specification via TEAD1 in the vascular organoids and human pluripotent stem cells-derived endothelium model

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Abstract

Background

We have shown that Hippo-YAP signaling pathway plays an important role in endothelial cell differentiation. Vestigial-like family member 4 (VGLL4) has been identified as a YAP inhibitor. However, the exact function of VGLL4 in vascular endothelial cell development remains unclear. In this study, we investigated the role of VGLL4, in human endothelial lineage specification both in 3D vascular organoid and 2D endothelial cell differentiation.

Methods and results

In this study, we found that VGLL4 was increased during 3D vascular organoids generation and directed differentiation of human embryonic stem cells H1 towards the endothelial lineage. Using inducible ectopic expression of VGLL4 based on the piggyBac system, we proved that overexpression of VGLL4 in H1 promoted vascular organoids generation and endothelial cells differentiation. In contrast, VGLL4 knockdown (heterozygous knockout) of H1 exhibited inhibitory effects. Using bioinformatics analysis and protein immunoprecipitation, we further found that VGLL4 binds to TEAD1 and facilitates the expression of endothelial master transcription factors, including FLI1, to promote endothelial lineage specification. Moreover, TEAD1 overexpression rescued VGLL4 knockdown-mediated negative effects.

Conclusions

In summary, VGLL4 promotes EC lineage specification both in 3D vascular organoid and 2D EC differentiation from pluripotent stem cell, VGLL4 interacts with TEAD1 and facilitates EC key transcription factor, including FLI1, to enhance EC lineage specification.

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Availability of data and materials

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank all members of the Institute of Hypoxia Medicine who contributed to this work. We appreciate the great help of Dr. Lei Zhang (Institute of Biochemistry and Cell Biology at the Chinese Academy of Sciences), Dr. Jiaxi Zhou (State Key Laboratory of Experimental Hematology in China), Dr. Bin Zhao (Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University), and Faxing Yu (School of Life Sciences, Fudan University) for this project.

Funding

This work was supported by the National Key Research and Development Program of China (2019YFA0802702), National Natural Science Foundation of China (82070487, 81670454, and 32070804), Natural Science Foundation of Zhejiang Province (LY21C120003), and Scientific Research Start-up Fund of Wenzhou Medical University (QTJ15029).

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Authors and Affiliations

  1. Institute of Hypoxia Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

    Yingyi Quan, Minjie Hu, Junming Fan, Xiaofang Fan, Yongsheng Gong & Yongyu Wang

  2. State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, 211116, Jiangsu, China

    Yingyi Quan, Jiang Jiang & Yang Yang

  3. Department of Cardiothoracic Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China

    Peifeng Jin

  4. Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

    Ming Li & Yongyu Wang

Authors
  1. Yingyi Quan
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  2. Minjie Hu
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  3. Jiang Jiang
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  4. Peifeng Jin
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Contributions

YW and YY contributed to the conception, design, and financial support of the study. YQ, MH, and JJ performed the experiments, analyzed and interpreted the data. JM, ML, JF, XF, and YG assisted with experiments. YW and YQ analyzed the data and wrote the manuscript. YW and YY edited the manuscript. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Yang Yang or Yongyu Wang.

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Conflict of interest

The authors declare that they have no competing interests.

Ethical approval and Consent to participate

This study was approved by the Medical Research Ethics Committee of Wenzhou Medical University (No.2019–214). The investigation conformed to the principles outlined in the Declaration of Helsinki.

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Not applicable.

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Quan, Y., Hu, M., Jiang, J. et al. VGLL4 promotes vascular endothelium specification via TEAD1 in the vascular organoids and human pluripotent stem cells-derived endothelium model. Cell. Mol. Life Sci. 80, 215 (2023). https://doi.org/10.1007/s00018-023-04858-w

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